DESCRIPTION (Applicant's abstract): Pulmonary fibrosis is a potentially lethal lung disorder characterized by fibroblast proliferation and excessive accumulation of extracellular matrix proteins, including fibronectin and types I and III collagen. As a consequence of matrix deposition, thickening of the alveolar septum and loss of functional alveolar capillaries can lead to impaired pulmonary function. The development of pulmonary fibrosis is a common response to acute injury and inflammation in the lung. Current therapies, however, have little effect on the progression of the disease. Fibronectin expression and deposition are markedly increased in tissues following injury, where it functions as a chemoattractant and adhesive molecule for migrating cells. Excess or inappropriate deposition of fibronectin into the extracellula matrix during the reparative phase of injury has been associated with fibrotic changes. Evidence suggests that polymerized fibronectin may serve as a templat for subsequent collagen deposition. However, the precise relationship between fibronectin polymerization and collagen synthesis and deposition during pulmonary fibrosis is not known. The goal of these studies is to elucidate the role of multimeric fibronectin in regulating cell migration, collagen synthesi and collagen deposition. Recombinant fibronectin fragments, which inhibit fibronectin polymerization in vitro, will be used to determine the relationshi between fibronectin polymerization and collagen deposition, in vitro and in vivo, using an animal model of fibrosis. These studies will provide informatio crucial to understanding the role of extracellular matrix fibronectin in regulating cell activities which contribute to the development of fibrosis. Elucidating the effect of fibronectin matrix assembly on cell behavior is central to designing methods of intervention during abnormal or altered fibronectin deposition, as occurs during fibrosis. As such, the overall aim of this proposal is to identify mechanisms which control and modulate fibronectin deposition in order to define strategies aimed at limiting the excess deposition of extracellular matrix during pulmonary fibrosis.